Heat-killed Mycobacterium tuberculosis induces trained immunity in vitro and in vivo administered systemically or intranasally.

Trained immunity (TI) represents a memory-like process of innate immune cells. TI can be initiated with various compounds such as fungal ß-glucan or the tuberculosis vaccine, Bacillus Calmette-Guérin. Nevertheless, considering the clinical applications of harnessing TI against infections and cancer, there is a growing need for new, simple, and easy-to-use TI inducers. Here, we demonstrate that heat-killed Mycobacterium tuberculosis (HKMtb) induces TI both in vitro and in vivo. In human monocytes, this effect represents a truly trained process, as HKMtb confers boosted inflammatory responses against various heterologous challenges, such as lipopolysaccharide (Toll-like receptor [TLR] 4 ligand) and R848 (TLR7/8 ligand). Mechanistically, HKMtb-induced TI relies on epigenetic mechanisms in a Syk/HIF-1α-dependent manner. In vivo, HKMtb induced TI when administered both systemically and intranasally, with the latter generating a more robust TI response. Summarizing, our research has demonstrated that HKMtb has the potential to act as a mucosal immunotherapy that can successfully induce trained responses.

Cell therapy for male sexual dysfunctions: systematic review and position statements from the European Society for Sexual Medicine.

Background: Cell therapy (CT) is a form of regenerative medicine under investigation for the management of male sexual dysfunction (MSD). Aim: We sought to perform a systematic review of published information on CT for MSD and provide an official position statements for the European Society for Sexual Medicine. Methods: A comprehensive bibliographic search on the MEDLINE, Web of Science, Scopus, and Cochrane Library databases was conducted in February 2023. Articles were selected based on the Population, Intervention, Comparator, Outcome, Study design (PICOS) model if they included male patients (P) undergoing CT (I) with or without comparison with other treatments (C) and evaluated the impact of CT on sexual function (O). Quantitative data were reported as found in the original studies (S). Level of evidence and grade of recommendation according to the Oxford Centre for Evidence-Based Medicine were assigned to each statement. Outcomes: Outcomes were determined based on assessment of erectile function, ejaculatory function, orgasmic function, sexual desire, and penile curvature. Results: A total of 19 studies and 421 patients were included. Most articles (n = 12, 63%) were case series, whereas a minority of papers (n = 6, 32%) had a comparative group; only 2 articles reported randomized controlled trials (RCTs) and 1 article reported a post hoc analysis of RCTs. Most articles (16, 84%) investigated patients with erectile dysfunction (ED). Improvements in the International Index of Erectile Function-Erectile Function Domain (IIEF-EF) or the IIEF 5-item version (IIEF-5) were found in 11/15 (73%) studies, with mean increases in IIEF-EF, mean IIEF-5, and median IIEF-EF between 8 and 14 points, 2 and 9 points, and 4.5 and 6 points, respectively. Two papers (20%) evaluated men with Peyronie's disease (PD). In both ot these articles penile curvature improvement and plaque volume reduction were described in all patients (n = 16, 100%). Objective measurements were performed in 1 study, which showed 10°-120° (15%-100%) curvature improvement and 90%-100% plaque reduction. Mild transient adverse events at the donor or administration sites were found in 7/16 (44%) papers on ED. Priapism was reported in one case (20%) and mild penile skin complications were reported in the majority of patients after CT for PD. No severe adverse events were described. Clinical Implications: Although high-quality evidence is lacking, CT appears to have potential benefits from application in patients with ED or PD. Strengths and Limitations: This report is to our knowledge the most comprehensive and up-to-date systematic review on the topic of CT for the management of MSD, including the position statements of the European Society for Sexual Medicine. Overall the assessment of available studies demonstrated low quality and significant heterogeneity. Conclusion: Preliminary findings support potential efficacy and safety of CT in patients with ED or PD. Low-quality papers, high methodological heterogeneity, uncertainty about the magnitude of the beneficial effects, and lack of long-term data limit the available evidence.

Spatial variability in herbaceous plant phenology is mostly explained by variability in temperature but also by photoperiod and functional traits.

Whereas temporal variability of plant phenology in response to climate change has already been well studied, the spatial variability of phenology is not well understood. Given that phenological shifts may affect biotic interactions, there is a need to investigate how the variability in environmental factors relates to the spatial variability in herbaceous species' phenology by at the same time considering their functional traits to predict their general and species-specific responses to future climate change. In this project, we analysed phenology records of 148 herbaceous species, which were observed for a single year by the PhenObs network in 15 botanical gardens. For each species, we characterised the spatial variability in six different phenological stages across gardens. We used boosted regression trees to link these variabilities in phenology to the variability in environmental parameters (temperature, latitude and local habitat conditions) as well as species traits (seed mass, vegetative height, specific leaf area and temporal niche) hypothesised to be related to phenology variability. We found that spatial variability in the phenology of herbaceous species was mainly driven by the variability in temperature but also photoperiod was an important driving factor for some phenological stages. In addition, we found that early-flowering and less competitive species characterised by small specific leaf area and vegetative height were more variable in their phenology. Our findings contribute to the field of phenology by showing that besides temperature, photoperiod and functional traits are important to be included when spatial variability of herbaceous species is investigated.

Survival Outcomes and Health-Related Quality of Life in Older Adults Diagnosed with Acute Myeloid Leukemia Receiving Frontline Therapy in Daily Practice.

Acute myeloid leukemia has a poor prognosis in older adults, and its management is often unclear due to its underrepresentation in clinical trials. Both overall survival (OS) and health-related quality-of-life (HRQoL) are key outcomes in this population, and patient-reported outcomes may contribute to patient stratification and treatment assignment. This prospective study included 138 consecutive patients treated in daily practice with the currently available non-targeted therapies (intensive chemotherapy [IC], attenuated chemotherapy [AC], hypomethylating agents [HMA], or palliative care [PC]). We evaluated patients' condition at diagnosis (Life expectancy [Lee Index for Older Adults], Geriatric Assessment in Hematology [GAH scale], HRQoL [EQ-5D-5L questionnaire], and fatigue [fatigue items of the QLQ-C30 scale]), OS, early death (ED), treatment tolerability (TT) and change in HRQoL over 12 months follow-up. The median OS was 7.1 months (IC not reached, AC 5.9, HMA 8.8, and PC 1.0). Poor risk AML category and receiving just palliative care, as well as a higher Lee index score in the patients receiving active therapy, independently predicted a shorter OS. The Lee Index and GAH scale were not useful for predicting TT. The white blood cell count was a valid predictor for ED. Patients' HRQoL remained stable during follow-up.

Patients' attitude with surgery for Peyronie's disease: results from a multicentric European study.

BACKGROUND: Despite the existence of conservative therapies for Peyronie's disease (PD), surgery is commonly utilized for the treatment of bothersome curvatures due to its potential effectiveness, although it carries intrinsic risks and may not universally lead to satisfactory outcomes. AIM: To explore the rate and factors influencing patients' willingness to undergo surgery for PD. METHODS: Data were prospectively collected in 5 European academic centers between 2016 and 2020. Data included age, time from PD onset, penile pain, curvature degree, difficulty at penetration, hourglass deformity, erectile dysfunction (ED), and previous treatments. All patients were offered conservative treatments, either medications or injections. Tunical shortening or lengthening procedures were offered as an alternative to conservative treatments, when indicated. Penile prosthesis was offered to those with concomitant ED. Patients' attitudes with surgery were recorded. Logistic regression analyses tested the profile of patients who were more likely to be willing to undergo surgery. OUTCOMES: Patients' willingness to undergo surgery for PD. RESULTS: This study included 343 patients with a median age of 57.3 years (IQR, 49.8-63.6) and a median penile curvature of 40.0° (IQR, 30.0°-65.0°). Overall, 161 (47%) experienced penetration difficulties and 134 (39%) reported ED. Additionally, hourglass deformity and penile shortening were reported by 48 (14%) and 157 (46%), respectively. As for previous treatments, 128 (37%) received tadalafil once daily; 54 (16%) and 44 (13%), intraplaque verapamil and collagenase injections; and 30 (9%), low-intensity shock wave therapy. Significant curvature reduction (≥20°) was observed in 69 (20%) cases. Only 126 (37%) patients were open to surgery for PD when suggested. At logistic regression analysis after adjusting for confounders, younger age (odds ratio [OR], 0.97; 95% CI, 0.95-1.00; P = .02), more severe curvatures (OR, 1.04; 95% CI, 1.03-1.06; P < .0001), and difficulty in penetration (OR, 1.88; 95% CI, 1.04-3.41; P = .03) were associated with a greater attitude to consider surgical treatment. CLINICAL IMPLICATIONS: The need for effective nonsurgical treatments for PD is crucial, as is comprehensive patient counseling regarding surgical risks and benefits, particularly to younger males with severe curvatures. STRENGTHS AND LIMITATIONS: Main limitations are the cross-sectional design and the potential neglect of confounding factors. CONCLUSIONS: Patients with PD, having a lower inclination toward surgery, emphasize the need for effective nonsurgical alternatives and accurate counseling on the risks and benefits of PD surgery, particularly for younger men with severe curvatures.

Habitat-based biodiversity responses to macroclimate and edaphic factors in European fen ecosystems.

Understanding large-scale drivers of biodiversity in palustrine wetlands is challenging due to the combined effects of macroclimate and local edaphic conditions. In boreal and temperate fen ecosystems, the influence of macroclimate on biodiversity is modulated by hydrological settings across habitats, making it difficult to assess their vulnerability to climate change. Here, we investigate the influence of macroclimate and edaphic factors on three Essential Biodiversity Variables across eight ecologically defined habitats that align with ecosystem classifications and red lists. We used 27,555 vegetation plot samples from European fens to assess the influence of macroclimate and groundwater pH predictors on the geographic distribution of each habitat type. Additionally, we modeled the relative influence of macroclimate, water pH, and water table depth on community species richness and composition, focusing on 309 plant specialists. Our models reveal strong effects of mean annual temperature, diurnal thermal range, and summer temperature on biodiversity variables, with contrasting differences among habitats. While macroclimatic factors primarily shape geographic distributions and species richness, edaphic factors emerge as the primary drivers of composition for vascular plants and bryophytes. Annual precipitation exhibits non-linear effects on fen biodiversity, with varying impact across habitats with different hydrological characteristics, suggesting a minimum requirement of 600 mm of annual precipitation for the occurrence of fen ecosystems. Our results anticipate potential impacts of climate warming on European fens, with predictable changes among habitat types and geographic regions. Moreover, we provide evidence that the drivers of biodiversity in boreal and temperate fens are closely tied to the ecological characteristics of each habitat type and the dispersal abilities of bryophytes and vascular plants. Given that the influence of macroclimate and edaphic factors on fen ecosystems is habitat specific, climate change research and conservation actions should consider ecological differentiation within functional IUCN ecosystems at continental and regional scales.

Global seed dormancy patterns are driven by macroclimate but not fire regime.

Seed dormancy maximizes plant recruitment in habitats with variation in environmental suitability for seedling establishment. Yet, we still lack a comprehensive synthesis of the macroecological drivers of nondormancy and the different classes of seed dormancy: physiological dormancy, morphophysiological dormancy and physical dormancy. We examined current geographic patterns and environmental correlates of global seed dormancy variation. Combining the most updated data set on seed dormancy classes for > 10 000 species with > 4 million georeferenced species occurrences covering all of the world's biomes, we test how this distribution is driven by climate and fire regime. Seed dormancy is prevalent in seasonally cold and dry climates. Physiological dormancy occurs in relatively dry climates with high temperature seasonality (e.g. temperate grasslands). Morphophysiological dormancy is more common in forest-dominated, cold biomes with comparatively high and evenly distributed precipitation. Physical dormancy is associated with dry climates with strong seasonal temperature and precipitation fluctuations (e.g. deserts and savannas). Nondormancy is associated with stable, warm and wetter climates (e.g. tropical rain forest). Pyroclimate had no significant effect on the distribution of seed dormancy. The environmental drivers considered in this study had a comparatively low predictive power, suggesting that macroclimate is just one of several global drivers of seed dormancy.

Fluorescent Dissolved Organic Matter Components as Surrogates for Disinfection Byproduct Formation in Drinking Water: A Critical Review.

Disinfection byproduct (DBP) formation, prediction, and minimization are critical challenges facing the drinking water treatment industry worldwide where chemical disinfection is required to inactivate pathogenic microorganisms. Fluorescence excitation-emission matrices-parallel factor analysis (EEM-PARAFAC) is used to characterize and quantify fluorescent dissolved organic matter (FDOM) components in aquatic systems and may offer considerable promise as a low-cost optical surrogate for DBP formation in treated drinking waters. However, the global utility of this approach for quantification and prediction of specific DBP classes or species has not been widely explored to date. Hence, this critical review aims to elucidate recurring empirical relationships between common environmental fluorophores (identified by PARAFAC) and DBP concentrations produced during water disinfection. From 45 selected peer-reviewed articles, 218 statistically significant linear relationships (R2 ≥ 0.5) with one or more DBP classes or species were established. Trihalomethanes (THMs) and haloacetic acids (HAAs), as key regulated classes, were extensively investigated and exhibited strong, recurrent relationships with ubiquitous humic/fulvic-like FDOM components, highlighting their potential as surrogates for carbonaceous DBP formation. Conversely, observed relationships between nitrogenous DBP classes, such as haloacetonitriles (HANs), halonitromethanes (HNMs), and N-nitrosamines (NAs), and PARAFAC fluorophores were more ambiguous, but preferential relationships with protein-like components in the case of algal/microbial FDOM sources were noted. This review highlights the challenges of transposing site-specific or FDOM source-specific empirical relationships between PARAFAC component and DBP formation potential to a global model.

Male Infertility and the Risk of Developing Testicular Cancer: A Critical Contemporary Literature Review.

Background and Objectives: The relationship between male infertility (MI) and testicular cancer (TC) is bilateral. On one hand, it is well-established that patients diagnosed with TC have a high risk of pre- and post-treatment infertility. On the other hand, the risk of developing TC in male infertile patients is not clearly defined. The objective of this review is to analyze the histopathological, etiological, and epidemiological associations between MI and the risk of developing testicular cancer. This review aims to provide further insights and offer a guide for assessing the risk factors for TC in infertile men. Materials and Methods: A comprehensive literature search was conducted to identify relevant studies discussing the relationship between MI and the risk of developing TC. Results: The incidence rates of germ cell neoplasia in situ (GCNIS) appear to be high in infertile men, particularly in those with low sperm counts. Most epidemiological studies have found a statistically significant risk of developing TC among infertile men compared to the general or fertile male populations. The concept of Testicular Dysgenesis Syndrome provides an explanatory model for the common etiology of MI, TC, cryptorchidism, and hypospadias. Clinical findings such as a history of cryptorchidism could increase the risk of developing TC in infertile men. Scrotal ultrasound evaluation for testis lesions and microlithiasis is important in infertile men. Sperm analysis parameters can be useful in assessing the risk of TC among infertile men. In the future, sperm and serum microRNAs (miRNAs) may be utilized for the non-invasive early diagnosis of TC and GCNIS in infertile men. Conclusions: MI is indeed a risk factor for developing testicular cancer, as demonstrated by various studies. All infertile men should undergo a risk assessment using clinical examination, ultrasound, and semen parameters to evaluate their risk of TC.

Voice Assistants as Consultants for Male Patients with Sexual Dysfunction: A Reliable Option?

The aim of this study was to evaluate the ability of Google Assistant, Alexa, and Siri to recognize and answer questions about male sexual health. Each VA was tested on a smart speaker: Alexa on Amazon Echo Dot 4th Gen., Google Assistant on Google Home Mini, and Siri on Apple HomePod. A pool of patients' frequently asked questions regarding erectile dysfunction (ED), premature ejaculation (PE), Peyronie's disease (PD), male infertility, and other aspects of male sexual health were identified by authors. The recognition of question was evaluated ("yes" or "not"). For each recognized question, the response characteristics (domains) were rated on a scale from 0 to 10 (according to the quality). We chose the recognition rate of the questions as the primary outcome and the quality of the answers as the secondary outcome. Overall, the best VA in recognizing questions was Siri, with a total of 83.3% questions compared with 64.0% for Alexa (p = 0.024) and 74.0% for Google Assistant (p = 0.061). Siri was associated with a significantly higher recognition rate than Alexa for PE (80% vs. 40%; p = 0.002) and PD (66.7% vs. 33.3%; p = 0.010). The quality of the responses was classified as low in 57 out of 105 cases (54.3%), intermediate in 46 cases (43.8%), and high in only 2 cases (1.9%), highlighting an overall intermediate-low quality of the answers. Male infertility was the condition associated with the highest mean scores in "Targeted response to the problem" (7.32 ± 2.57), "Scientific correctness of the answer", (5.9 ± 2.76) "Completeness of the answer" (5.14 ± 2.56), and "Understandability of the response for a patient" (5.3 ± 2.51) domains. Siri was associated with significantly higher scores than Alexa (p < 0.05) in several domains of all conditions evaluated. The question recognition rate of VAs is quite high; however, the quality of the answers is still intermediate-low. Siri seems superior to Alexa in both question recognition and response quality. Male infertility appears to be the sexual dysfunction best addressed by VAs.

Treatments for multi-system inflammatory syndrome in children - discharge, fever, and second-line therapies.

Scarce evidence exists about the best treatment for multi-system inflammatory syndrome (MIS-C). We analyzed the effects of steroids, intravenous immunoglobulin (IVIG), and their combination on the probability of discharge over time, the probability of switching to second-line treatment over time, and the persistence of fever 2 days after treatment. We did a retrospective study to investigate the effect of different treatments on children with MIS-C from 1 March 2020 to 1 June 2021. We estimated the time-to-event probability using a Cox model weighted by propensity score to balance the baseline characteristics. Thirty of 132 (22.7%) patients were initially treated with steroids alone, 29/132 (21.9%) with IVIG alone, and 73/132 (55%) with IVIG plus steroids. The probability of early discharge was higher with IVIG than with IVIG plus steroids (hazard ratio [HR] 1.65, 95% CI 1.11-2.45, p = 0.013), but with a higher probability of needing second-line therapy compared to IVIG plus steroids (HR 3.05, 95% CI 1.12-8.25, p = 0.028). Patients on IVIG had a higher likelihood of persistent fever than patients on steroids (odds ratio [OR] 4.23, 95% CI 1.43-13.5, p = 0.011) or on IVIG plus steroids (OR 4.4, 95% CI 2.05-9.82, p < 0.001). No differences were found for this endpoint between steroids or steroids plus IVIG.    Conclusions: The benefits of each approach may vary depending on the outcome assessed. IVIG seemed to increase the probability of earlier discharge over time but also of needing second-line treatment over time. Steroids seemed to reduce persistent fever, and combination therapy reduced the need for escalating treatment. What is Known: • Steroids plus intravenous immunoglobulin, compared with intravenous immunoglobulin alone for multi-system inflammatory syndrome (MIS-C) might reduce the need for hemodynamic support and the duration of fever, but the certainty of the evidence is low. What is New: • Intravenous immunoglobulin, steroids, and their combination for MIS-C may have different outcomes. • In this study, intravenous immunoglobulin increased the probability of discharge over time, steroids reduced persistent fever, while combination therapy reduced the need for second-line treatments.

Low availability of functional seed trait data from the tropics could negatively affect global macroecological studies, predictive models and plant conservation.

BACKGROUND: Plant seeds have many traits that influence ecological functions, ex situ conservation, restoration success and their sustainable use. Several seed traits are known to vary significantly between tropical and temperate regions. Here we present three additional traits for which existing data indicate differences between geographical zones. We discuss evidence for geographical bias in availability of data for these traits, as well as the negative consequences of this bias. SCOPE: We reviewed the literature on seed desiccation sensitivity studies that compare predictive models to experimental data and show how a lack of data on populations and species from tropical regions could reduce the predictive power of global models. In addition, we compiled existing data on relative embryo size and post-dispersal embryo growth and found that relative embryo size was significantly larger, and embryo growth limited, in tropical species. The available data showed strong biases towards non-tropical species and certain families, indicating that these biases need to be corrected to perform truly global analyses. Furthermore, we argue that the low number of seed germination studies on tropical high-mountain species makes it difficult to compare across geographical regions and predict the effects of climate change in these highly specialized tropical ecosystems. In particular, we show that seed traits of geographically restricted páramo species have been studied less than those of more widely distributed species, with most publications unavailable in English or in the peer-reviewed literature. CONCLUSIONS: The low availability of functional seed trait data from populations and species in the tropics can have negative consequences for macroecological studies, predictive models and their application to plant conservation. We propose that global analyses of seed traits with evidence for geographical variation prioritize generation of new data from tropical regions as well as multi-lingual searches of both the grey- and peer-reviewed literature in order to fill geographical and taxonomic gaps.

Current clinical spectrum of common variable immunodeficiency in Spain: The multicentric nationwide GTEM-SEMI-CVID registry.

Common variable immunodeficiency (CVID) constitutes a heterogenic group of primary immunodeficiency disorders with a wide-ranging clinical spectrum. CVID-associated non-infectious morbidity constitutes a major challenge requiring a full understanding of its pathophysiology and its clinical importance and global variability, especially considering the broad clinical, genetic, and regional heterogeneity of CVID disorders. This work aimed to develop a nationwide, multicenter, retrospective study over a 3-year period describing epidemiological, clinical, laboratory, therapeutic, and prognostic features of 250 CVID patients in Spain. The mean diagnostic delay was around 10 years and most patients initially presented with infectious complications followed by non-infectious immune disorders. However, infectious diseases were not the main cause of morbimortality. Non-infectious lung disease was extraordinarily frequent in our registry affecting approximately 60% of the patients. More than one-third of the patients in our cohort showed lymphadenopathies and splenomegaly in their follow-up, and more than 33% presented immune cytopenias, especially Evans' syndrome. Gastrointestinal disease was observed in more than 40% of the patients. Among biopsied organs in our cohort, benign lymphoproliferation was the principal histopathological alteration. Reaching 15.26%, the global prevalence of cancer in our registry was one of the highest reported to date, with non-Hodgkin B lymphoma being the most frequent. These data emphasize the importance of basic and translational research delving into the pathophysiological pathways involved in immune dysregulation and diffuse lymphocytic infiltration. This would reveal new tailored strategies to reduce immune complications, and the associated healthcare burden, and ensure a better quality of life for CVID patients.

mpMRI-US Fusion-Guided Targeted Cryotherapy in Patients with Primary Localized Prostate Cancer: A Prospective Analysis of Oncological and Functional Outcomes.

Targeted therapy (TT) for prostate cancer (PCa) aims to ablate the malignant lesion with an adequate margin of safety in order to obtain similar oncological outcomes, but with less toxicity than radical treatments. The main aim of this study was to evaluate the recurrence rate (RR) in patients with primary localized PCa undergoing mpMRI/US fusion targeted cryotherapy (FTC). A secondary objective was to evaluate prostate-specific antigen (PSA) as a predictor of recurrences. We designed a prospective single-center single-cohort study. Patients with primary localized PCa, mono or multifocal lesions, PSA ≤ 15 ng/mL, and a Gleason score (GS) ≤ 4 + 3 undergoing FTC were enrolled. RR was chosen as the primary outcome. Recurrence was defined as the presence of clinically significant prostate cancer in the treated areas. PSA values measured at different times were tested as predictors of recurrence. Continuous variables were assessed with the Bayesian t-test and categorical assessments with the chix-squared test. Univariate and logistic regression assessment were used for predictions. A total of 75 cases were included in the study. Ten subjects developed a recurrence (RR: 15.2%), while fifty-six (84.8%) patients showed a recurrence-free status. A %PSA drop of 31.5% during the first 12 months after treatment predicted a recurrence with a sensitivity of 53.8% and a specificity of 79.2%. A PSA drop of 55.3% 12 months after treatment predicted a recurrence with a sensitivity of 91.7% and a specificity of 51.9%. FTC for primary localized PCa seems to be associated with a low but not negligible percentage of recurrences. Serum PSA levels may have a role indicating RR.

Organocatalytic Enantioselective α-Bromination of Aldehydes with N-Bromosuccinimide.

Despite the wealth of existing organocatalytic, enantioselective transformations, the α-bromination of aldehydes remains a challenging reaction. The four examples reported to date require expensive, inconvenient brominating agents to achieve the desired products in excellent yields and enantioselectivities. The preferred brominating agent, N-bromosuccinimide (NBS), has been repeatedly discarded for these reactions because it results in low yields and relatively poor enantioselectivities. We describe a methodology that uses NBS and performs excellently with low catalyst loadings, short reaction times, and mild temperatures.